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European Review for Medical and Pharmacological Sciences
2010; 14: 969-978
Cardiac resynchronization therapy: could a
numerical simulator be a useful tool in order
to predict the response of the biventricular
pacemaker synchronization?
C. DE LAZZARI1,2, A. D’AMBROSI3, F. TUFANO3, L. FRESIELLO2, M. GARANTE3,
R. SERGIACOMI3, F. STAGNITTI3, C.M. CALDARERA2, N. ALESSANDRI2,3
1
C.N.R., Institute of Clinical Physiology, U.O.S. of Rome (Italy)
Istituto Nazionale per le Ricerche Cardiovascolari, Bologna (Italy)
3
U.O.C. of Cardiology of the University “Sapienza”, Polo Pontino, Latina (Italy)
2
Abstract. – Background and Objectives:
Cardiac resynchronization therapy (CRT) can be
considered as an established therapy for patients with moderate or severe heart failure (HF),
depressed systolic function and a wide QRS
complex. Biventricular stimulation through the
CRT is applied at patients with an intra and/or inter-ventricular conduction delay. The goal of this
technique is to resynchronize contraction between and within ventricles.
A numerical model of the cardiovascular system, together with the numerical model of the
biventricular pacemaker (BPM), can be an useful
tool to study the better synchronization of the
BPM in order to reduce the inter-ventricular
and/or intra-ventricular conduction delay.
Subjects and Methods: Within a group of
patients which were representative of the most
common disease etiologies of heart failure,
seven patients, affected by dilated cardiomyopathy undergoing CRT with BPM, were studied
and simulated using the numerical model of the
cardiovascular system CARDIOSIM ©. The patients were submitted to echocardiographic
evaluation (with pulsate Doppler and tissue
Doppler imaging) and electrocardiography evaluation in order to evaluate intra-ventricular
and/or inter-ventricular dyssynchrony. These
evaluations were made three times: the first
one before BPM implantation, the second and
the third one respectively within seven days
and six months after BPM implantation. Also
haemodynamic parameters were measured. Using the software simulator, the pathological
conditions before CRT, within seven days and
within six months since CRT were reproduced
for each patients in order to evaluate the following haemodynamic parameters: the end-systolic and end-diastolic left ventricular volume,
the systolic pulmonary arterial pressure, the
systolic, diastolic and mean aortic blood pressure and the ejection fraction. Also the trend of
the left ventricular elastance was studied for
each patient in order to evaluate the benefits
produced by the CRT.
Results: The results obtained by means the
numerical simulator were in good agreement
with clinical data measured on the patients. For
each patient also the evolution of the left ventricular elastance was in accordance with the literature data.
Conclusion: The cardiovascular numerical
model seems to be a useful tool to study the
synchronization of the BPM in order to reduce
the inter-ventricular and/or intra-ventricular conduction delay and to reproduce the condition of
a patient.
Key Words:
Cardiac resynchronization therapy, Circulatory system,
Haemodynamics, Computer simulation.
Introduction
Dilated cardiomyopathy is a disease that produces an enlarged heart that does not pump properly. It is the most common reason for prescribing cardiac resynchronization therapy (CRT).
CRT can be considered a promising treatment
in some patients with moderate or severe heart
failure (HF), depressed systolic function and a
wide QRS complex. CRT can reduce left ventricular end systolic volume, improve left ventricular
systolic function and increase ejection fraction
(EF)1-3.
CRT is a technique for the treatment of moderate or severe HF associated with electro-
Corresponding Author: Claudio De Lazzari, ENG; e-mail: [email protected]
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C. De Lazzari, A. D’Ambrosi, F. Tufano, L. Fresiello, M. Garante, et al.
mechanical dyssynchrony. In particular, for patients belonging to New York Heart Association
(NYHA) Class III or IV heart failure and intraventricular conduction delay, randomized controlled trials have shown that CRT improves
symptoms of heart failure, quality of life, exercise capacity, left ventricular ejection fraction
(LVEF), and reduces all-cause mortality. CRT is
responsible for the “reverse remodelling” which
consists of a gradual reduction of left ventricular dilation (negative ventricular remodelling).
The mechanisms of “reverse remodelling” yield
the reduction of: (1) the regional wall stress, (2)
the myocardial oxygen consumption, (3) the
sympathetic tone, (4) the progression of mitral
regurgitation4,5.
Biventricular stimulation through the CRT is
applied to patients affected by left ventricular
failure with an intra-ventricular conduction delay
due to asynchronous ventricular contraction5.
The aim of CRT is to resynchronize contraction between and within ventricles.
Conventional biventricular pacemaker (BPM)
has three leads placed in the right atrium, in the
right ventricle and in a vein on the surface of the
left ventricle. To solve the inter-ventricular
and/or intra-ventricular conduction delay, the
synchronization of the BPM must be specific for
each patient, in order to obtain the better ventricular synchronization6.
A numerical model of the cardiovascular system together with the numerical model of the
BPM can be an useful tool to help physicians to
optimize the synchronization of the BPM in order to reduce the inter-ventricular and/or intraventricular conduction delay7,8.
In this paper a numerical simulator of the cardiovascular system (CARDIOSIM©), able to reproduce inter-ventricular and/or intra-ventricular
interactions, was used to reproduce in terms of
haemodynamic parameters the conditions of seven patients affected by dilated cardiomyopathy
before and after BPM implantation9-11. The patients were submitted to echocardiographic evaluation before CRT, within seven days and within
six months since CRT. In all patients the measured echocardiographic parameters were: aortic
(pulmonary) pre-ejection time, septal to lateral
wall motion delay, end-systolic and end-diastolic
left ventricular volume (ESV, EDV), systolic pulmonary arterial pressure and ejection fraction.
The measured electrocardiographic parameters
were: PQ, QRS and QT duration. The measured
haemodynamic parameters were: heart rate (HR)
970
and systolic and diastolic blood pressure (BPS
and BPD). The simulator reproduces the end-systolic and end-diastolic left ventricular volume,
the systolic pulmonary arterial pressure (PAPS),
the systolic (BPS), the diastolic (BPD), the mean
(AoP) blood pressure and the EF (%) in pathological conditions and after BPM implantation.
In addition the simulator predicts the trend of the
left ventricular elastance.
Materials and Methods
In the U.O.C. of Cardiology of the University
“Sapienza”, Rome (Italy), seven patients were selected (within a group of patients featuring the
most common disease etiologies of heart failure),
five males and two females affected by dilated
cardiomyopathy undergoing CRT with BPM.
Five patients were affected by idiopathic heart
failure, one patient was affected by ischaemic
heart failure and one was affected by valvular
heart failure. All patients had left ventricular dysfunction with ejection fraction less than 35% and
the QRS duration greater than 0.12 sec. These
patients were evaluated before and after BPM
implantation, in particular 24h since CRT, seven
days and six months since CRT, with electrocardiography and echocardiography method. After
CRT, the effects of BPM were evaluated. In all
patients the following clinical parameters were
assessed: heart rate (HR), body weight, systolic
and diastolic blood pressure (BP S and BP D).
Electrocardiography parameters as PQ, QRS and
QT duration were measured too. In addition, all
patients were analyzed by means of echocardiography with pulsate Doppler and tissue Doppler
imaging, in order to evaluate intra and inter-ventricular dyssynchrony. The morphologic echocardiography parameters measured were: end-systolic and end-diastolic left ventricular volume
(ESV, EDV), ejection fraction EF(%), thickness
inter-ventricular septum (IVS). The Doppler parameters taken into account were also systolic
pulmonary arterial pressure (PAPs), aortic and
pulmonary pre-ejection time an septal to lateral
wall motion delay. These last parameters were
measured in order to evaluate the inter and intraventricular delay respectively12.
The measured echocardiographic, electrocardiographic and haemodynamic parameters before
and after BPM implantation are listed in Tables
Ia, II and III respectively.
M
M
F
F
M
M
M
75
82
78
70
86
67
63
Age
76
75
68
80
70
64
65
HR
[beats/min]
1
2
3
4
5
6
7
76
75
68
80
70
64
65
HR
[beats/min]
90
110
110
130
100
110
100
90.7
112
110
130.5
99
109.7
100.4
BPS
[mmHg]
58.3
59
71.7
88
72.2
79.3
62.8
BPD
[mmHg]
70
77
83
100
80
90
73
AoP
[mmHg]
60
60
70
85
70
80
60
BPD
[mmHg)
Before CRT
BPS
[mmHg]
Before CRT
Table Ib. Simulated parameters.
1
2
3
4
5
6
7
Sex
Table Ia. Clinical parameters
75
75
66
75
70
68
70
94
100
100
120
100
123
105
BPS
[mmHg]
92.8
101.5
101
119.2
101.9
121.2
102.2
BPS
[mmHg]
62
61.5
61.8
81.9
61.7
76.4
64.4
BPD
[mmHg]
62
60
60
80
60
75
60
73
73
73
93
73
91
75
73
73
73
93
73
91
75
75
75
64
70
80
70
70
95
110
100
110
100
120
110
60
70
60
70
60
75
70
BPD
[mmHg]
91.4
109.6
101.4
110
102
125.8
111.3
BPS
[mmHg]
60.9
69.7
61.6
71.8
61
72.8
72.3
BPD
[mmHg]
Within 6 months since CRT
75
75
64
70
80
70
70
BPS
[mmHg]
Within 6 months since CRT
HR
[beats/min]
HR
[beats/min]
AoP
[mmHg]
AoP
[mmHg]
BPD
[mmHg]
Within 7 days since CRT
75
75
66
75
70
68
70
HR
[beats/min]
HR
[beats/min]
70
77
83
100
80
90
73
AoP
[mmHg]
Within 7 days since CRT
72
83
73
83
73
90
83
AoP
[mmHg]
72
83
73
83
73
90
83
AoP
[mmHg]
Cardiac resynchronization therapy
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192 (213)
139 (201)
105 (160)
110 (170)
78 (105)
115 (160)
127 (177)
167 (204)
153 (225)
95 (160)
94 (150)
52 (80)
105 (155)
127 (177)
130 (169)
145 (215)
86 (153)
90 (150)
46 (85)
94 (154)
120 (171)
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
ESV
(EDV)
[ml]
(Measured)
Table II.
129.96 (171.20)
144.29 (216.22)
85.90 (153.3)
90.10 (151.7)
45.97 (85.15)
94.11 (152.72)
120.86 (171.23)
164.31 (205.57)
152.36 (225.85)
95.95 (162.96)
93.98 (151.55)
51.42 (80.88)
103.13 (152.85)
127.05 (177.27)
190.58 (213.17)
139.43 (200.53)
104.2 (159.63)
110.37 (170.84)
78.59 (106.11)
115.28 (162.5)
144.19 (186.08)
ESV
(EDV)
[ml]
(Simulated)
55
60
40
40
40
45
40
55
65
40
40
35
50
40
60
60
45
50
30
60
50
Systolic
Pulmonary
Arterial
Pressure (PAPs)
[mmHg]
(Measured)
20
3
25
30
10
14
20
44.8
65 (44)
40 (23.9)
40 (23.9)
40 (26)
29.7
40 (28)
20
10
20
25
0
9
10
Within 6 months since CRT
43.7
67 (49.3)
40 (24.1)
40 (23.9)
35 (27.6)
39.8
40 (28.5)
Within 7 days since CRT
60 (44.6)
60 (48.7)
45 (26)
50 (32.2)
30 (22.3)
60 (43.9)
50 (35.1)
20
28
50
45
34
30
37
Interventricular
Delay
[ms]
(Measured)
Before CRT
PAPs
(mean PAP)
[mmHg]
(Simulated)
20
20
25
20
6
20
8
25
20
25
20
12
20
32
70
50
60
60
37
50
50
Intraventricular
Delay
[ms]
(Measured)
23
33
44
40
46
39
30
18
32
41
37
35
32
28
10
31
34
35
25
28
23
EF
[%]
(Measured)
24.1
33.3
44.2
40.6
46
38.4
29.4
20.1
32.5
40.9
38
36.4
39.8
28.3
10.6
30.5
34.8
35.4
25.9
29
22.5
EF
[%]
(Simulated)
C. De Lazzari, A. D’Ambrosi, F. Tufano, L. Fresiello, M. Garante, et al.
Cardiac resynchronization therapy
Table III. ECG parameters.
Before CRT
1
2
3
4
5
6
7
Within 7 days since CRT
Within 6 months since CRT
QRS [ms]
QT [ms]
PQ [ms]
QRS [ms]
QT [ms]
PQ [ms]
QRS [ms]
QT [ms]
PQ [ms]
180
140
150
150
120
140
140
340
420
410
420
400
410
400
180
220
180
FA
180
160
160
120
180
130
130
120
130
130
370
400
420
420
400
400
410
160
200
180
FA
180
160
160
120
160
140
130
120
130
130
370
420
420
430
420
410
410
160
180
180
FA
180
160
160
Starting from the measured data a human
numerical simulator of the cardiovascular system CARDIOSIM© was used in order to reproduce the patient conditions. This software can
simulate physiopathological circulatory phenomena in terms of pressures, volumes and
flows CARDIOSIM © has a modular structure
(Figure 1) that includes9-11:
Figure 1. Electric analogue of the numerical simulator. MV (AV) and Rli (Rlo) represent the mitral (aortic) valve. TV (PV) and Rri
(Rro) represent the tricuspid (pulmonary) valve. Rlv (Rrv) is the left (right) ventricular internal resistance. Qli (Qri) is the input flow
of the left (right) ventricle, Qlo (Qro) is the output flow of the left (right) ventricle, Qlia (Qria) is the input flow of the left (right) atrium. Pla (Pra) is the left (right) atrial pressure, Plv (Prv) is the left (right) ventricular pressure, Pas (Pap) is the systemic (pulmonary)
arterial pressure, Pvs (Pvp) is the systemic (pulmonary) venous pressure. Pt is the mean intrathoracic pressure.
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• the systemic arterial (pulmonary) section modelled by a modified windkessel with a characteristic resistance Rcs (Rcp), a inertance Ls
(Lp), a compliance Cas (Cap) and a variable
peripheral resistance Ras (Rap);
• the systemic venous section modelled by a
compliance Cvs and the variable resistance
Rvs;
• the pulmonary venous section modelled by a
simple compliance Cv;
• the coronary section;
• the left and the right heart.
In the simulator, the behaviour of both atria is
described by variable elastance models and their
mechanical properties are related the ECG
signal13. Figure 2 shows the schematic representation of the ECG signal used in the software. Also ventricles are described by variable elastance
models reproducing the Starling’s law of the
heart13.
In order to simulate also the intraventricular
dyssynchrony, a model of the ventricular interaction (or “ventricular interdependence”)
was implemented reproducing the behaviour
of the septum by the time-varying elastance
model7,14.
The pathological conditions of the patients
were reproduced by setting model parameters as
reported below:
• in order to obtain the measured systolic (BPS)
and diastolic (BPD) systemic arterial pressure,
Ras was automatically calculated using a
dedicated algorithm implemented in the simulator10;
• knowing Ras, BPS, BPD and the timing constant, also Cas was estimated;
• septum systolic (diastolic) elastance was calculated starting from systolic (diastolic) septum thickness measured by ECO;
• left ventricular systolic (diastolic) elastance was
set in order to place the left ventricular loop in
the pressure-volume plane, knowing the measured ESV, EDV. To place the left ventricular
loop it has also been assumed that the left ventricular end systolic pressure can be approximated with mean aortic pressure value15;
• heart rate (HR) was set as the measured value;
• from ECG signal, QT, PQ and QRS were measured and then inserted in the model of ECG
implemented in the software;
• finally the interventricular and intra-ventricular delay were set staring from the data measured by ECO.
After BPM implantation, the patient conditions were simulated programming the BPM according to the temporizations chosen by physicians and setting the software parameters in the
way previously described.
Figure 2. Schematic representation of the electrocardiogram (ECG) signal. The period (TT-TTE) represents the ventricular systole duration the period (TPB-TPE) corresponds to the atrial systole duration.
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The reproduced parameters were: the end-systolic and end-diastolic left ventricular volume
(ESV, EDV), the systolic pulmonary arterial
pressure (PAPs), the systolic (BP S), diastolic
(BPD) and mean (AoP) blood pressure and the EF
(%). The software simulator can, also, predict the
trend of the cardiac contractility when the CRT is
applied.
Results
Table Ia (Ib) reports the following clinical
haemodynamic (simulated) parameters: HR, systolic blood pressure (BPS), diastolic blood pressure (BPD) and the mean blood pressure (AoP).
Table II shows measured and simulated echocardiographic parameters: end-systolic and end-diastolic left ventricular volume (ESV, EDV), systolic pulmonary arterial pressure (PAPs), inter
and intra-ventricular delay and ejection fraction
(EF). All data were measured and simulated before and after BPM implantation.
Figure 3 shows one of the different possible
graphical and numerical output produced by
the software simulator CARDIOSIM©. In figure, for the patient #5, the haemodynamic conditions before (A) and six months since (B)
BPM implantation are reproduced. The commands section of the software is shown in the
left column. In the central upper (A) and lower
(B) windows, the left ventricular loops, in the
pressure-volume plane, before and six months
since CRT respectively are reproduced. In the
two right columns the values of: HR, mean
pressures (calculated in the cardiac cycle), systolic (BPS) and diastolic (BPD) blood pressure
and mean flow are reported. The two boxes under these columns show the inter and intraventricular delays before (A) and after (B)
BPM implantation. Finally in the two boxes
Figure 3. Screen output produced by the software simulator. For the patient #5, the haemodynamic conditions before (A) and
six months since (B) BPM implantation are reproduced. In the pressure-volume plain the cardiac cycle of the left ventricle has
been represented. ESPVR (EDPVR) is the end systolic (end diastolic) pressure volume relationship line. In the screen software
representation Pas is the mean (evaluated during the cardiac cycle) systolic arterial pressure, Pap is the mean pulmonary arterial pressure, Qlia (Qria) is the input flow of the left (right) atrium. Ves (Ved) represents the end systolic (diastolic) ventricular
volume, SV is the stroke volume. “LV-Septum Delay” represents the intra-ventricular delay time and “LV-RV Delay” represents
the inter-ventricular delay time. Vlv is the left ventricular volume.
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under the pressure-volume windows the endsystolic and the end-diastolic ventricular volumes, the stroke volumes and the ejection fractions, for both ventricles, are reproduced. In
order to evaluate the effects of CRT on the cardiac contractility, it has been analyzed the
trend of the left ventricular systolic elastance
(that is the slope of the ESPVR – Figure 3) estimated by the software simulator. Figure 4
shows the trend of left ventricular systolic
elastance (that is an index of cardiac contractility) for all patients before and after CRT.
left ventricular volume reduction and increase of
the EF (Table II). In the echocardiography with
pulsate Doppler and tissue Doppler imaging it
was measured a reduction of intra and inter-ventricular delays (Table II).
In most of the patients studied the best simulated left ventricular systolic elastance was observed after six months from BPM implantation16 (Figure 4). However the patient 4 shows
the best simulated results within seven days
since CRT.
The results reported about the patient 2
shows that CRT within seven days has not produced an improvement in haemodynamic variables (Table II). In fact after BPM implantation
it is possible to observe an increase of ESV
and EDV, but the EF is increased because also
the SV improvement. The data obtained by the
software simulator show a reduction in left
ventricular systolic elastance (Figure 4). This
effect due to the displacement of the ventricular loop to increasing ventricular volume
Discussion
The haemodynamic and echocardiographic parameters analysed in this study show an improvement trend after six months from BPM implantation. In all patients it was observed a rising in
morphologic echocardiography parameters with
Left ventricular systolic elastance
1
0.8
0.6
0.4
0.2
0
#1
#2
#3
#4
#5
#6
#7
Before CRT
Within 7 days since CRT
Within 6 months since CRT
Figure 4. The trend of left ventricular systolic elastance (obtained by the software simulator) for all patients is reported. For
each patient a set of three different values before, within seven days since CRT and within six months since CRT respectively,
have been showed. For each set of data a normalization respect to the maximum elastance value has been done. In patient #1
maximum elastance value was obtained within six month since CRT. In patient #4 maximum elastance value was obtained
within seven days since CRT has been done.
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Cardiac resynchronization therapy
(Table II) and from mean blood pressure reduction (Table Ia). After six months since CRT
it was measured a reduction of ESV and EDV
respect to the measured value “within seven
days since CRT” but not respect to before
BPM implantation (Table II). Simulated data
show an improvement in left ventricular systolic elastance (respect to before BPM implantation) justified not by the ESV and EDV values but by the increase of the mean blood pressure (Table Ia).
In patients 5 the CRT seem to produce the
better improvement in terms of haemodynamic
parameters (Tables Ia and II) and in terms of intra and inter-ventricular delays (Table II). Figure 3 shows in the left ventricular pressure-volume plain the evolution of the ventricular loops
before (A) and within six months since CRT (B)
simulated by CARDIOSIM©. Two important effects can be evidenced: the first one regards the
shift of the loop in the lower volume direction
(B) with the consequent reduction of EDS and
EDV, the second one regards the ESPVR slope
that increase its value during the simulation regarding the patient conditions induced by CRT
after six month from BPM implantation (B). Finally in Figure 3, according to the literature16,
also a reduction in mean left atrial pressure
(preload) can be observed.
In conclusion the numerical model of the
cardiovascular system was able to reproduce
the pathological conditions of the patients and
the changes induced by the presence of biventricular pacemaker. In addition, the software
simulator can be used to evaluate the trend of
the cardiac contractility before and after CRT.
An improvement in the software could help the
physicians in programming of the BPM.
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